KR102509950B1 - Boron-containing proteasome inhibitors for use after primary cancer therapy - Google Patents

Abstract

The present disclosure relates to a method for treating cancer, or preventing recurrence or progression of cancer, or a dosing regimen comprising a proteasome inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, wherein rings A, Z ¹ and Z ² are as defined herein.
[Formula I]

Description

BORON-CONTAINING PROTEASOME INHIBITORS FOR USE AFTER PRIMARY CANCER THERAPY}

priority claim

This application is based on U.S. Provisional Application No. 62/000,991, filed on May 20, 2014, U.S. Provisional Application No. 62/019,600, filed on July 1, 2014, and U.S. Provisional Application No. 5, filed on December 5, 2014. Priority is claimed to 62/088,154. The entire contents of the aforementioned applications are hereby incorporated by reference.

Field of the Invention

The present disclosure relates to a method for treating cancer, or preventing recurrence or progression of cancer, or a dosing regimen comprising a proteasome inhibitor of Formula I.

Cancer has a major impact on society in the United States and worldwide. Cancer is the second most common cause of death in the United States, surpassed only by heart disease, accounting for nearly one in four deaths. The National Cancer Institute estimates that approximately 1,658,370 new cases of cancer will be diagnosed in the United States in 2015, and 589,430 people will die from the disease. Although medical advances have improved cancer survival rates, there is a continuing need for new and more effective treatments.

Multiple myeloma, a B-cell tumor of malignant plasma cells in the bone marrow, is considered incurable despite advances in new therapies using proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and stem cell transplant (SCT) therapies. Remains. Multiple myeloma is characterized by the accumulation of plasma cells in the bone marrow (and other organs) and can lead to bone marrow failure, bone destruction, hypercalcemia, and renal failure. Multiple myeloma constitutes approximately 1% of all neoplastic and approximately 13% of hematological cancers reported worldwide. In the United States, Canada, and Western European countries, approximately 5 to 7 new cases of multiple myeloma are diagnosed per 100,000 people each year. Palumbo and Anderson, N Engl J Med 2011;364(11):1046-60; Landgren and Weiss, Leukemia 2009;23(10):1691-7; Harousseau, et al ., Annals of Oncology 2008;19 Suppl 2:ii55-7. Although less common in Asian countries, the incidence of multiple myeloma has increased nearly four-fold over the past 25 years, and is characterized by a younger age of onset, more invasive disease, and a more unfavorable prognosis (Huang, et al., Cancer 2007; 110(4):896-905;Qiu, et al., Clinical Epidemiological Study on Multiple Myeloma in China (ASH Annual Meeting Abstracts) 2008;112(11):abstr 2723).

Multiple myeloma is sensitive to a number of cytotoxic drugs, including alkylating agents, anthracyclines, and corticosteroids, both for initial treatment and for recurrent disease. Over the past decade, significant progress has been made in expanding treatment options for multiple myeloma with new therapies such as thalidomide, bortezomib, and lenalidomide. These therapies prolonged progression-free survival (PFS) and/or time-to-progression (TTP) (Palumbo, et al., Leukemia 2008; 22(2) :414-23; Mateos, et al., Journal of Clinical Oncology 2010; 28(13):2259-66; Gay, et al., Haematologica 2010; 94:0507; Richardson, et al., Hematology 2007:317- 23; Dimopoulos, et al., Leukemia 2009; 23(11):2147-52). The introduction of new therapies and the increasing use of high-dose therapy (HDT) is helping patients with newly diagnosed multiple myeloma (NDMM) amenable to autologous stem cell transplant (ASCT). significantly improved overall survival (Kumar, et al., Blood 2008; 111(5):2516-20; Brenner, et al., Blood 2008; 111(5):2521-6; Libby, et al., Declining myeloma mortality rates in the United States following introduction of novel therapies In: International Myeloma Workshop Paris, France; 2011).

Despite more treatment options, multiple myeloma remains incurable, and patients with early-stage cancer remain at risk for recurrence after initial therapy. If patients relapse after initial therapy, they show variable response to subsequent therapy, reducing the duration of response (DOR) and likelihood. Patients become refractory to approved therapies, and ultimately no alternative treatment options remain. A need exists for new and better drugs and therapies that improve patient survival and/or reduce recurrence of cancer after completion of primary treatment. The methods of the present disclosure present new options to cancer patients.

The present disclosure relates to methods or dosing regimens for treating cancer or preventing recurrence or progression of cancer. The method or dosing regimen comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient receiving first-line cancer therapy on a dosing schedule comprising at least four 28-day treatment cycles,

[Formula I]

The 28-day treatment cycle is such that the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered once a week for the first 3 weeks of the treatment cycle and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered in 4 including 4 consecutive weeks of no administration during the first week, wherein ring A is

이고;

ego;

Z ¹ and Z ² are each independently hydroxyl; Z ¹ and Z ² together form a cyclic boric acid ester having 2 to 20 carbon atoms and optionally one or more heteroatoms selected from N, S, or O.

In certain aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered orally.

In certain aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each treatment cycle.

In certain aspects, the dosing schedule includes about 26 treatment cycles.

In certain aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered as a first dose for at least 4 treatment cycles and as a second dose for 5 to 26 treatment cycles.

In certain aspects, the first dose is about 1.5 mg/week to about 3.0 mg/week and the second dose is about 2.3 mg/week to about 4.0 mg/week for each of 3 weeks of the 4 week treatment cycle.

In certain aspects, the first dose of the present disclosure is about 3.0 mg/week and the second dose is about 4.0 mg/week, or the first dose is about 3.0 mg/week and the second dose is about 3.0 mg/week and 2 doses are about 3.0 mg/week, or the first dose is about 2.3 mg/week and the second dose is about 3.0 mg/week, or the first dose is about 2.3 mg/week and the second dose is about 2.3 mg/week , or the first dose is about 1.5 mg/week and the second dose is about 2.3 mg/week, or the first dose is about 1.5 mg/week and the second dose is about 1.5 mg/week. In certain aspects, the first dose is about 3.0 mg/week and the second dose is about 4.0 mg/week for each of 3 weeks of the 4 week treatment cycle.

In certain aspects, the first dose and the second dose are the same.

In certain aspects, the dosing schedule comprises up to about 26 treatment cycles, and the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered at about 3.0 mg/week from 1 treatment cycle to 26 treatment cycles.

In certain aspects, the compound of Formula I of the present disclosure is a compound of Formula IV: or an ester or pharmaceutically acceptable salt thereof:

[Formula IV]

In certain aspects, the compound of Formula I of the present disclosure is a compound of Formula IIIa, or a pharmaceutically acceptable salt thereof:

[Formula IIIa]

In certain aspects, the compound of Formula IV is administered in the form of an ester.

In certain aspects, the compound of Formula IV is administered in the form of a compound of Formula IIIa.

In certain aspects, the disclosure provides maintenance therapy comprising a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof, to treat cancer or prevent recurrence or progression of cancer, wherein the cancer is a hematological malignancy am.

In certain aspects, the disclosure provides maintenance therapy comprising a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof, to prevent progression of cancer in a cancer patient suffering from a primary cancer, wherein the cancer is a hematological malignancy. it is a tumor

In certain aspects, the present disclosure provides maintenance therapy to prevent recurrence or recurrence of multiple myeloma in cancer patients receiving first-line cancer therapy.

In certain aspects, the present disclosure provides maintenance therapy for cancer patients diagnosed with multiple myeloma or refractory multiple myeloma.

In certain aspects, the present disclosure provides maintenance therapy to prevent progression of multiple myeloma in cancer patients receiving first-line cancer therapy.

In certain aspects, the present disclosure provides maintenance therapy for treating patients who have, are at risk of developing, or are experiencing a relapse of a proteasome-mediated disorder.

In certain aspects, the present disclosure provides maintenance therapy for treating a patient who has, is at risk of developing, or is suffering a recurrence of a cancer selected from multiple myeloma.

In certain aspects, the present disclosure provides capsules comprising a compound of Formula IIIa.

Figure 1 shows the results of exposure-response analysis of safety and efficacy in patients with relapsed refractory multiple myeloma enrolled in a phase 1 study.
Figure 2: Best overall response in 21 patients (n=21) who received ixazomib maintenance therapy. The number on the bar represents the percentage of patients. Complete response (CR) or better reached 52% of patients. Very good partial response (VGPR) or better reached 71% of patients. 2 VGPR to near-CR (nCR), 5 VGPR to CR, 1 VGPR to stringent complete response (sCR), and 2 CR to sCR response improvement, including 48% improved response during maintenance.

The present disclosure provides various methods for treating cancer or preventing recurrence or progression of cancer. In a first aspect, the disclosure provides administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a cancer patient. In another aspect, the disclosure provides a dosing schedule of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as maintenance therapy for patients who have received and responded to primary cancer therapy. In a further aspect, the disclosure provides maintenance therapy comprising a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof, to improve and maintain response in patients receiving first-line cancer therapy.

In another aspect, the disclosure provides maintenance therapy comprising a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof, to prevent recurrence or progression of cancer in a patient.

In another aspect, the disclosure provides maintenance therapy comprising a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof, to prevent recurrence or progression of cancer.

In another aspect, the disclosure provides a maintenance therapy comprising a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof, to treat cancer or prevent recurrence or progression of cancer, wherein the cancer is haematologically is a malignant tumor

In another aspect, the disclosure provides maintenance therapy comprising a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof, to treat relapsed multiple myeloma, or to prevent relapse or progression of relapsed multiple myeloma. .

In another aspect, the disclosure provides maintenance therapy comprising a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof, to treat refractory multiple myeloma or to prevent relapse or progression of refractory multiple myeloma. .

In another aspect, the disclosure provides maintenance therapy comprising a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof, to treat newly diagnosed multiple myeloma, or to prevent recurrence or progression of newly diagnosed multiple myeloma. to provide.

In another aspect, the disclosure provides maintenance therapy to prevent progression of newly diagnosed multiple myeloma, comprising a proteasome inhibitor of Formula IIIa.

In another aspect, the disclosure provides a pharmaceutical composition containing a proteasome inhibitor of Formula IIIa, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the cancer is a hematological malignancy.

In certain embodiments, the hematological malignancy is multiple myeloma, mantle cell lymphoma, follicular cell lymphoma, T-cell lymphoma, peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulin it is blood

In certain embodiments, the hematological malignancy is mantle cell lymphoma, follicular cell lymphoma, T-cell lymphoma, peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's macroglobulinemia.

In certain embodiments, the hematological malignancy is amyloidosis. In certain embodiments, the hematological malignancy is systemic chain amyloidosis.

In certain embodiments, the cancer is newly diagnosed.

In certain embodiments, the cancer has relapsed.

In certain embodiments, the cancer is refractory.

In certain embodiments, the cancer is relapsed or refractory multiple myeloma.

In certain embodiments, the cancer is newly diagnosed multiple myeloma.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Accordingly, the following terms are intended to have the following meanings:

The term “maintenance therapy” refers to a treatment regimen designed to assist the success of primary treatment. For example, maintenance chemotherapy can be given to people whose cancer is in remission in an effort to prevent or delay relapse or reduce the likelihood of disease recurrence or progression. Maintenance therapy may be given for any length of time, including extended periods of time into the life of the subject. Maintenance therapy may be given after the initial treatment or with treatment or additional treatment. Dosages used for maintenance therapy may vary and may include lower intensity dosages compared to dosages used for other types of therapy, eg, first-line therapy (ie, first-line therapy, induction therapy). there is.

The term "primary treatment" refers to initial treatment given to a patient based on a diagnosis of the patient's disease. A diagnosis of a disease can be the first occurrence of the disease in a patient, ie a newly diagnosed patient, or a recurrence of the disease in a patient, ie a relapsed patient. Diagnosis is often part of a standard set of treatments, and optionally first-line treatment includes autologous stem cell transplantation. When used alone, first-line treatment is the one that is accepted as the best treatment. If the primary treatment does not cure the disease or causes serious side effects, other treatments may be added or used instead. The term is also known to those skilled in the art as first line treatment when referring to initial treatment of newly diagnosed patients, or as induction treatment, initial treatment, or primary treatment, each of which is initial treatment of newly diagnosed patients or relapsed patients. of the initial treatment.

The term “induction treatment” refers to the first stage of treatment for cancer. The goal of induction therapy for multiple myeloma is to reduce the number of plasma cells and the proteins they produce in the bone marrow. Induction treatment can include 3 to 4 weeks as one treatment cycle.

The term "autologous stem cell transplant" refers to stem cells that are collected from an individual and returned to the same individual. Stem cell transplantation is a procedure used in conjunction with high-dose chemotherapy, which is often more effective than conventional chemotherapy in destroying myeloma cells. High-dose chemotherapy also destroys normal blood-producing stem cells in the bone marrow, so these cells must be replaced to restore blood cell production.

The term "low intensity dose" refers to a regimen in which the dose is reduced compared to the dose regimen in first line treatment. In certain embodiments, the proteasome inhibitor of Formula I is reduced by less than 20%, 30%, 40%, 50%, 60%, 70% of the dosing regimen in the first treatment, for example up to a dose of 5.5 mg. do.

In certain embodiments, the reduced dosage is from about 3.0 mg to about 1.5 mg.

In certain embodiments, the reduced dosage is 3.0 mg, 2.3 mg, or 1.5 mg.

The term “survival” refers to a patient still alive and includes progression-free survival (PFS) and overall survival (OS). Survival can be estimated by the Kaplan-Meier method, and any variance in survival is calculated using a stratified log-rank test.

The term “progression free survival (PFS)” refers to the time from treatment (or randomization) to first disease progression or death. For example, progression-free survival is defined as, without initiation of treatment or return to cancer from an initial diagnosis (e.g., at a defined time, such as about 1 month, 2 months, 3 months, 3.5 months, 4 months, 5 months, 6 months). months, 7 months, 8 months, 9 months, about 1 year, about 2 years, about 3 years, about 5 years, about 10 years, about 15 years, about 20 years, about 25 years, etc.) the time the patient is still alive am. Progression-free survival can be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST).

The term “overall survival” refers to a defined time from initiation of treatment or initial diagnosis (e.g., about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, about 15 years, about 20 years). years, about 25 years, etc.) while the patient is still alive.

The term "proteasome-mediated disorder" refers to any disorder, disease or condition caused by or characterized by an increase in proteasome expression or activity, or requiring proteasome activity to sustain the condition. The term "proteasome-mediated disorder" also includes any disorder, disease or condition in which inhibition of proteasome activity is beneficial.

For example, the compounds and pharmaceutical compositions of the present disclosure may be used in the treatment of disorders mediated through proteins regulated by proteasome activity (eg, NFκB, p27 ^Kip , p21 ^WAF/CIP1 , p53) such as cancer. useful. As used herein, the term "cancer" refers to uncontrolled or unregulated cell proliferation, reduced cell differentiation, inadequate ability to invade surrounding tissue, and/or new growth at an ectopic site. refers to a cellular disorder characterized by the ability to establish The term “cancer” includes, but is not limited to, solid tumors and hematological tumors (hematologic malignancies). The term “cancer” includes diseases of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" further includes primary and metastatic cancers.

Non-limiting examples of hematological malignancies include amyloidosis, acute myeloid leukemia (AML); chronic myelogenous leukemia (CML) including accelerated CML and CML blast phase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS) such as refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), refractory with increased myeloblasts refractory anemia with excess blasts (RAEB), and refractory anemia with increased myeloblasts in transformation (RAEB in transformation; RAEB-T); and myeloproliferative syndrome.

The following phrase pairs are interchangeable: a compound of formula I and a proteasome inhibitor of formula I, a compound of formula IIIa and a proteasome inhibitor of formula IIIa; and compounds of formula IV and proteasome inhibitors of formula IV.

In cancer treatment, efficacy can be measured by assessing duration of survival, duration of progression-free survival (PFS), response rate (RR) to treatment, duration of response, and/or quality of life.

An example of an immunomodulatory drug (a drug that modulates the immune system) is an analog of thalidomide. Examples of drugs that modulate immunity include lenalidomide and pomalidomide.

Proteasome inhibitors are drugs that block the action of the proteasome, a cellular complex that degrades proteins such as p53. Proteasome inhibitors are being studied in the treatment of cancer, particularly multiple myeloma. Examples of proteasome inhibitors are bortezomib, carfilzomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, ONX0912, CEP-18770, and epoxomicin.

Additional examples of proteasome inhibitors are bortezomib, ixazomib, carfilzomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, ONX0912, CEP-18770, and epoxomicin.

In certain embodiments, the proteasome inhibitor is bortezomib.

In certain embodiments, the proteasome inhibitor is ixazomib or ixazomib citrate.

In certain embodiments, the proteasome inhibitor is carfilzomib.

The term “about” is used herein to mean approximately, approximately, or around an area. When the term “about” is used in conjunction with a numerical range, the term modifies the range by extending the boundaries above and below the stated numerical value. In general, the term "about" is used herein to modify a number above and below a stated value by a variation of 10%.

The term “comprises” refers to “including but not limited to”.

The term "pharmaceutically acceptable carrier" is used herein to refer to a substance compatible with a receptor, preferably a mammal, more preferably a human, and which is capable of delivering an active agent to a target site without terminating the activity of the active agent. suitable for conveying Toxicity or side effects associated with the carrier, if any, are preferably commensurate with a reasonable harm/benefit ratio for the intended use of the active agent.

Pharmaceutical compositions of the present disclosure may be prepared by methods well known in the art, such as conventional granulation, mixing, dissolution, encapsulation, lyophilization, or emulsification processes, among others. The composition may be produced in a variety of forms including granules, precipitates, particulates, or powders.

The term "orally" refers to administering a composition intended to be ingested. Examples of oral forms include, but are not limited to, tablets, pills, capsules, powders, granules, solutions or suspensions, and drops. Such forms may be swallowed whole or may be chewable.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is combined with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) a filler or bulking agent, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain a buffering agent such as a phosphate or carbonate salt.

The solid compositions can also be employed as fillers in soft and hard gelatin-filled capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with shells and coatings such as enteric coatings and other coatings well known in the pharmaceutical formulation art. The solid dosage form may optionally contain an opacifying agent and may also be of a composition such that the solid dosage form releases the active ingredient(s) only, or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. . Examples of embedding compositions that can be used include polymeric materials and waxes.

In solid dosage forms, the active ingredient may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, as is conventional practice, additional substances other than inert diluents, for example tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also contain a buffering agent.

The active ingredient may also be in microencapsulated form with one or more excipients as noted above.

The terms "boronate ester" and "boronic acid ester" are used interchangeably and refer to a -B(Z ¹ )(Z ² ) moiety, wherein Z ¹ and Z ² together are a ring having from 2 to 20 carbon atoms. form boric acid esters), and optionally one or more heteroatoms selected from N, S, or O.

In certain embodiments, the proteasome inhibitor of Formula I, or a pharmaceutically acceptable salt, stereoisomer or tautomeric form thereof, refers to the formula:

[Formula I]

during the ceremony,

ring A is

ego;

Z ¹ and Z ² are each independently hydroxyl; Z ¹ and Z ² together form a cyclic boric acid ester having 2 to 20 carbon atoms and optionally one or more heteroatoms selected from N, S, or O.

In certain embodiments, the proteasome inhibitor of Formula I is characterized by Formula Ia, or a pharmaceutically acceptable salt, stereoisomer or tautomeric form thereof:

[Formula Ia]

during the ceremony,

Z ¹ and Z ² are each independently hydroxyl; Z ¹ and Z ² together form a cyclic boric acid ester having 2 to 20 carbon atoms and optionally one or more heteroatoms selected from N, S, or O.

In certain embodiments, the proteasome inhibitor of Formula I is characterized by Formula II: or a pharmaceutically acceptable salt, stereoisomer or tautomeric form thereof:

[Formula II]

during the ceremony,

Ring A is as defined above; R ¹ and R ² are independently -(CH ₂ ) _p -CO ₂ H; One of the carboxylic acids optionally forms an additional bond with the boron atom; n is 0 or 1; p is 0 or 1;

In certain embodiments, the proteasome inhibitor of Formula I is characterized by Formula III: or a pharmaceutically acceptable salt, stereoisomer or tautomeric form thereof:

[Formula III]

wherein Ring A is as defined above.

In one embodiment, the proteasome inhibitor of Formula I is a compound of Formula IIIa, or a pharmaceutically acceptable salt, stereoisomer or tautomeric form thereof:

[Formula IIIa]

In one embodiment, the proteasome inhibitor of Formula IIIa is in substantially crystalline form.

In one embodiment, the proteasome inhibitor of Formula I is a compound of Formula IV: or an ester or pharmaceutically acceptable salt thereof:

[Formula IV]

.

.

Synthetic methods for the preparation of proteasome inhibitors of Formulas I, II, III, IIIa and IV are well known in the art and are described in, for example, US Pat. Nos. 7,442,830, 7,687,662, US Pat. US Patent No. 8,530,694, and International Patent Publication WO 2009/154737, which are specifically and entirely incorporated herein by reference.

The compound of formula IV, also known as ixazomib, is a peptide boric acid developed by Millennium Pharmaceuticals, Inc. Ixazomib is a biologically active molecule that potently, reversibly and selectively inhibits the proteasome. The compound of formula IIIa is the citrate ester of ixazomib, referred to herein as ixazomib citrate. Ixazomib citrate rapidly hydrolyzes to ixazomib upon contact with plasma or aqueous solutions. In contrast to the first of its kind, the small molecule proteasome inhibitor Bortezomib (VELCADE®), ixazomib exhibits a faster rate of dissociation from the proteasome, possibly leading to improved tumor penetration and , exhibits antitumor activity in a wider range of tumor xenografts, and has more prolonged tissue penetration.

Ixazomib preferentially binds to the β5 site of the 20S proteasome at a concentration (IC ₅₀ ) of 3.4 nM, which represents 50% inhibition. At higher concentrations, ixazomib also inhibits the activity of the β1 and β2 sites. Ixazomib inhibits the proteasome when tested against a panel of proteases (IC ₅₀ values between 20 and 100 μM), kinases (IC ₅₀ values greater than 10 μM), and receptors (IC ₅₀ values greater than 10 μM). It is optional. Ixazomib and bortezomib have different β5 proteasome dissociation half-lives (t _1/2 ), which reflects the difference in their on-off association rates (β5 proteasome for ixazomib citrate and bortezomib). Dissociation [t _1/2 ] is 18 min and 110 min, respectively) (Kupperman E, et al. Cancer Res 2010;70:1970-1980).

Ixazomib has been evaluated in clinical studies involving patients with late-stage solid tumors, lymphomas, relapsed/refractory multiple myeloma (RRMM), or relapsed or refractory light chain (AL) amyloidosis, and has shown early signs of activity. The data suggest a favorable toxicity profile with a low rate of peripheral neuropathy (PN). Richardson PG, et al. Blood 2014; 124:1038-1046. Kumar SK, et al. Blood 2014; 124:1047-1055. Ongoing studies continue to investigate both ixazomib as a single agent and ixazomib in combination with standard of care. An additional clinical study will evaluate ixazomib in combination with placebo/rendex versus lenalidomide and dexamethasone (LenDex) at a dose of ixazomib 4 mg weekly. A recent safety profile indicates that ixazomib is generally well tolerated (Kumar S, et al. Blood 2012;119:4375-4382. Richardson PG, et al. Blood; 2010;116:679-686. Jakubowiak AJ, et al. Blood 2012;120:1801-1809).

To select an appropriate dose for the ixazomib maintenance study, Applicants conducted exposure-response analysis of safety and efficacy data from patients with relapsed refractory multiple myeloma enrolled in a phase 1 study of weekly single agent ixazomib. performed. The assay was designed to yield an initial estimate of the biologically active exposure-dose range of ixazomib associated with disease control and acceptable tolerability, thereby maintaining adequate tolerability during long-term treatment while maintaining drug exposure in the biologically active range. to secure The methods and results of this assay are described below.

Exposure/Efficacy Analysis

Safety (S) and efficacy (E) data from patients enrolled in a phase 1 study of weekly single agent ixazomib in relapsed and refractory multiple myeloma were used (N=44). The range of ixazomib doses investigated was 1 to 8.9 mg. Metric units of exposure (Ex) were AUC per day for both exposure logistic regression analysis Ex/S and Ex/E (derived from individual clearance values using population pharmacokinetics). Ex/S analysis was performed for 7 adverse events (AEs): non-hematological (non-H) adverse events (fatigue, rash, peripheral neuropathy, diarrhea) and hematological (H) adverse events (anemia). , thrombocytopenia, neutropenia). Non-hematologic adverse event reporting data were grouped into a grade of 2 or greater versus grade of 1 or less, while hematological adverse event reporting data were grouped into a grade of 3 or greater versus a grade of 2 or less. Data were disaggregated this way because maintenance therapy has an acceptable adverse event reporting profile and contributes to an acceptable quality of life. Because reports of Grade 3 hematologic adverse events have less impact on quality of life and are more manageable than reports of Grade 2 non-haematological adverse events, such as diarrhea, different cut-offs are applied for hematologic and non-haematological adverse events. used for reporting. For exposure efficacy (Ex/E), data were categorized as stable disease (SD) versus progressive disease (PD). Clinical benefit ratios, including SE achieved in relapsed or refractory patients, can be important predictors of expected response in a maintenance setting. Logistic regression analysis was performed using SPLUS software version 8.1.

The results of the logistic regression analysis showed that, among the 7 evaluated AEs, a statistically significant relationship (p<0.05) for Ex was observed for 5 AEs (fatigue, rash, diarrhea, thrombocytopenia, neutropenia). and clinical benefit ratios (SD or higher) were shown. At a starting dose of 3.0 mg weekly (54% of MTD), the model had an SD abnormality of approximately 33% and an incidence of grade 2 or greater in non-H AEs (rash 16%, diarrhea 19% and fatigue 19%), and in AEs Predict grade 3 or higher (neutropenia 10%, thrombocytopenia 22%). In addition, the 3.0 mg dose is within the therapeutic range and represents a dose level below the starting dose used in the ongoing phase 3 trial in patients with relapsed refractory and previously untreated multiple myeloma.

Figure 1 illustrates the relationship of patient exposure to the response (clinical benefit and safety) of ixazomib dose. Figure 1 shows that favorable benefit versus harm can be achieved at weekly doses of 3.0 mg and 4.0 mg below the maximum tolerated dose. Therefore, in maintenance therapy, patients can start with ixazomib at a once-weekly dose of 3.0 mg, which can be increased to 4.0 mg providing maximum clinical benefit if acceptable tolerability is determined after 4 cycles.

maintenance therapy

Maintenance therapy is long-term therapy intended to prolong the duration of a patient's response to first-line therapy. Long-term maintenance therapy improves survival outcomes, including progression-free survival and sometimes overall survival, in both transplant and non-transplant settings. However, agents for sustained therapy must be convenient and well tolerated. The balance of benefits versus harms is paramount in maintenance therapy. The prerequisites for successful maintenance therapy are good long-term tolerability and adherence to the regimen (low discontinuation rates due to toxicity and ease of administration), demonstration of clinical benefit in both prolonging survival or improving quality of life without shortening survival, and Include a favorable benefit/harm ratio. Although there is emerging evidence of the clinical benefit of maintenance therapy after stem cell transplantation/therapy, the balance of positive benefits and harms in existing therapies has not yet been established. To date, there are no drugs approved for maintenance in patients with newly diagnosed multiple myeloma and in patients with relapsed refractory multiple myeloma.

In one embodiment, the maintenance therapy of the present disclosure comprises administering a compound of Formula IIIa (ixazomib citrate) to a patient with newly diagnosed multiple myeloma who has already undergone induction therapy and a single autologous stem cell transplant. include

In one embodiment, the maintenance therapy of the present disclosure comprises administering a compound of Formula IIIa (ixazomib citrate) to patients with newly diagnosed multiple myeloma who have already received induction therapy and one or more autologous stem cell transplants. Include steps.

In one embodiment, the maintenance therapy of the present disclosure contains a high-dose therapy such as melphalan (200 mg/m ² ) and a single autologous stem cell transplant followed by induction therapy according to local standards of care for patients with newly diagnosed multiple myeloma. administering a compound of Formula IIIa (ixazomib citrate) to a patient who has already undergone a conditioning regimen for Induction therapy should include proteasome inhibitors and/or immunomodulatory drug-based therapy.

In certain embodiments, the induction therapy includes a proteasome inhibitor, wherein the proteasome inhibitor is ixazomib or ixazomib citrate.

In one embodiment, the maintenance therapy of the present disclosure comprises administering a compound of Formula IIIa (ixazomib citrate) to a patient with newly diagnosed multiple myeloma who has already received induction therapy but not an autologous stem cell transplant. includes

In certain embodiments, patients who achieve clinical and hematological recovery after induction therapy, high-dose therapy, and autologous stem cell transplant will initiate screening for maintenance therapy eligibility within 75 days post transplant and screening within 15 days post transplant and will be randomized within 115 days post transplant. Eligible patients (patients with complete remission, very good partial remission, or partial remission documented on induction therapy during screening) may be treated with ixazomib maintenance therapy. stratification factor, induction therapy (proteasome inhibitor without immunomodulatory drug, drug-modulated drug without proteasome inhibitor, proteasome inhibitor and immunomodulatory drug); pre-guided International Staging System (ISS) (stage 1 versus stage 2 or 3); and post-transplant response (complete response, very good partial response, or partial response), defined as response after induction therapy, high-dose therapy, and autologous stem cell transplantation measured during screening.

In certain embodiments, patients with newly diagnosed multiple myeloma who respond (complete remission, very good partial remission, or partial remission) to high-dose therapy and autologous stem cell transplant after induction therapy may be treated with ixazomib maintenance therapy. .

In certain embodiments, patients with newly diagnosed multiple myeloma who respond (complete response, very good partial response, or partial response) to autologous stem cell transplant after induction therapy may be treated with ixazomib maintenance therapy.

In certain embodiments, patients with newly diagnosed multiple myeloma who respond (complete response, very good partial response, or partial response) to induction therapy and have not received a stem-cell transplant may be treated with ixazomib maintenance therapy.

In certain embodiments, the maintenance therapy of the present disclosure comprises administering a compound of Formula IIIa (ixazomib citrate) to a patient with a hematological malignancy who has already received induction therapy.

In certain embodiments, the maintenance therapy of the present disclosure comprises administering a compound of Formula IIIa (ixazomib citrate) to a patient with a hematological malignancy who has already undergone induction therapy and one or more autologous stem cell transplants. includes

In certain embodiments, the maintenance therapy of the present disclosure comprises administering a compound of Formula IIIa (ixazomib citrate) to a patient with a hematological malignancy who has already received induction therapy but not an autologous stem cell transplant. include

In certain embodiments, induction therapy includes a chemotherapy regimen. Examples of such chemotherapeutic regimens are CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-EPOCH ( etoposide, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), HyperCVAD with or without rituximab (cyclophosphamide alternating methotrexate and cytarabine, vincristine , doxorubicin, dexamethasone), or VADs (vincristine, doxorubicin, dexamethasone).

In certain embodiments, induction therapy includes proteasome inhibitors and/or immunomodulatory drug-based therapy.

In a specific embodiment, the patient is administered an ixazomib citrate capsule orally once a week for 3 consecutive weeks, then the 1 week elapses without the capsule. This 4-week (28-day) dosing regimen includes one treatment cycle. In certain embodiments, the patient is administered one capsule of ixazomib citrate on days 1, 8, and 15 of a 28-day cycle.

In certain embodiments, the proteasome inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, is administered as a first dose for at least 4 treatment cycles and is administered as a second dose for 5 to 26 treatment cycles.

In one embodiment, the first dose strength of ixazomib in the form of ixazomib citrate capsules, 3.0 mg/week, will be used in patients in the first to fourth treatment cycles. After assessment of toxicity at the completion of the 4th treatment cycle, the patient will receive a second dose of ixazomib at an increased dose strength of 4.0 mg/week starting with cycles 5 through 26 treatment cycles, for the duration of maintenance therapy. Administration on the same schedule for cycles 1 to 4 of treatment will provide the greatest possible clinical benefit in patients surviving the first 4 cycles of treatment.

In one embodiment, the first dose strength of ixazomib in the form of ixazomib citrate capsules will be used from patients starting the first treatment cycle. If the patient tolerates the first dose intensity, the patient will record a second dose at the dose intensity intensified at any time point in the assessment of toxicity after the first dose.

In a first embodiment, a first dose strength of ixazomib in the form of ixazomib citrate capsules of 3.0 mg/week will be used in patients starting from the first treatment cycle. If the patient tolerates the 3.0 mg/week dose strength, the patient may receive a second dose at an increased dose strength of 4.0 mg/week at any time in the assessment of toxicity after the first dose.

In one embodiment, the first dose strength of ixazomib in the form of ixazomib citrate capsules of 4.0 mg/week will be used in patients starting from the first treatment cycle. If the patient tolerates the 4.0 mg/week dose intensity, the patient can continue at the 4.0 mg/week dose intensity.

In one embodiment, the first dose of ixazomib 3.0 mg/week in the form of ixazomib citrate capsules will be used in patients in the first through fourth treatment cycles. Upon completion of the 4th treatment cycle and assessment of toxicity, patients unable to tolerate the increased dose intensity are maintained at the starting dose intensity of 3.0 mg/week for 26 treatment cycles in the 5th treatment cycle and treatment cycle 1 for the duration of maintenance therapy. will be administered on the same schedule from 4 to 4.

In certain embodiments, patients who experience adverse event reports during any treatment cycle may continue on maintenance therapy, but have the ixazomib dose reduced or maintained by at least one dose level. In certain embodiments, the reduced dose is from about 3.0 mg to about 1.5 mg. In certain embodiments, the reduced dose is 3.0 mg, 2.3 mg, and 2.5 mg.

The treatment period of the maintenance therapy is defined as any time point at which the patient receives the proteosome inhibitor of Formula I of the present disclosure and will include a 28 day treatment cycle. In certain embodiments, the patient will perform treatment assessments at regular treatment cycle intervals while the patient is participating in therapy: every week (days 1, 8 and 15) during cycle 1, during cycle 2. Twice per treatment cycle (days 1 and 8), and once per treatment cycle for the remainder of participation in the next treatment cycle, until the patient suffers discontinuous or progressive disease for alternative reasons.

In certain embodiments, the patient is discontinuous prior to each cycle during treatment and thereafter every 4 weeks during progression-free survival on maintenance therapy or prior to the follow-up period to progression to progressive disease, according to the International Myeloma Working Group. It will be evaluated for disease response and progression before the next line of therapy. After progressive disease, patients will be followed for an overall survival follow-up period. Patients will initially be followed every 4 weeks until initiation of the next line of therapy by the treating physician. All patients will then be followed every 12 weeks until death or end of therapy. During the overall survival follow-up period, patients and their treating physicians will be contacted regarding health-related quality of life (until the initiation of the next line of therapy only), disease status, and survival for evaluation of the next line of therapy. . Health-related quality of life (HRQL) will be assessed through a patient self-report mechanism from the time of randomization to the time of initiation of the next line of therapy. After progression and after initiation of the next line of therapy, determination of disease response and progression will be assessed by the treating physician according to International Myeloma Research Council criteria.

In certain embodiments, adverse event reports will be evaluated, and laboratory values, vital signs, and electrocardiograms (ECGs) will be obtained to assess the safety and toxicity of ixazomib. Toxicity will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03 (Effective Date: June 14, 2010).

In certain embodiments, therapeutic efficacy will be measured. Changes measured in patients between the initial and subsequent time points indicate that maintenance therapy is therapeutically effective.

In certain embodiments, the first time point can be, eg, before administration, after day 1 of administration, after day 5 of administration, at the start of a treatment cycle, at the end of a treatment cycle, and the like. Regardless of when the first point in time is, the second point in time is after the first point in time.

During the course of treatment, patient data may be collected and used to evaluate the efficacy of treatment. Relevant data includes pharmacokinetic data.

In certain embodiments, the patient has either a documented progression of disease (according to criteria of the International Myeloma Research Group) or intolerable toxicity for a maximum period of approximately 24 months (to the nearest complete cycle, 26 cycles). You will receive maintenance therapy until it appears first.

In certain embodiments, the patient will receive maintenance therapy for approximately 24 months. In certain embodiments, the patient will receive maintenance therapy until documented disease progression (per the criteria of the International Myeloma Research Council) or intolerable toxicity. In certain embodiments, the patient will receive clinically indicated You will receive one maintenance treatment (more than 26 cycles).

In certain embodiments, patients completing a 24-month treatment cycle focused on tolerability and symptom relief, clinical, laboratory, response, and weight-related quality of life, as well as minimal residual disease assessments will be made. After documented disease progression, subsequent therapy will be determined by the treating physician.

In certain embodiments, a response (complete response, very ^good partial response, or Partial remission) Adult patients 18 years of age or older with a confirmed diagnosis of multiple myeloma will be eligible for maintenance therapy.

In certain embodiments, patients who meet the following criteria are eligible for maintenance therapy:

a. Adult male or female patients 18 years of age or older with confirmed symptomatic multiple myeloma.

b. Recorded results of cytogenetic/fluorescence in situ hybridization (FISH) obtained at any time prior to transplantation and, if possible, International Staging System staging at time of diagnosis.

c. After receiving treatment-guided therapy/standard of first-line therapy (therapy must include proteasome inhibitors and/or immunomodulatory drug-based therapy as first-line therapy for multiple myeloma), high-dose melphalan (200 mg/day) within 12 months of diagnosis m ² ) Received a single autologous stem cell transplant with conditioning therapy.

d. Screening started within 75 days post transplant, screening completed within 15 days, randomization within 115 days post transplant.

e. Patients may not receive consolidation therapy after autologous stem cell transplantation.

f. Response to autologous cell transplantation (partial response, very good partial response, complete response/strict complete response).

g. Eastern Cooperative Oncology Group performance status is 0 to 2.

In certain embodiments, patients who meet the following criteria are eligible for maintenance therapy:

a. Adult male or female patients 18 years of age or older with a confirmed diagnosis of newly diagnosed multiple myeloma presenting with symptoms according to standard criteria.

2주) 완료.b. 6 to 12 months of initial therapy, while the patient is being treated with the best response, defined as the best response maintained for 2 cycles after reaching the trough of the M-protein

2 weeks) done.

c. Documentation of primary response (partial remission, very good partial remission, complete remission according to the International Myeloma Research Group's (IMWG) uniform response criteria, version 2011 after initial therapy).

In certain embodiments, active ixazomib is given to the patient in strengths of 4.0 mg, 3.0 mg, 2.3 mg, and 1.5 mg.

In certain embodiments, ixazomib is administered to the patient as ixazomib citrate in a solid dose capsule.

In certain embodiments, the ixazomib citrate capsules in maintenance therapy contain various dosage strengths, including 0.5 mg, 2.3 mg, 3.0 mg, or 4.0 mg of ixazomib. Pharmaceutical compositions containing ixazomib citrate and a pharmaceutically acceptable carrier of the present disclosure can be prepared by methods well known in the art, for example, International Patent Publication WO 2009/154737, which is specifically and entirely incorporated herein by reference. It can be prepared by the method described in).

In certain embodiments, ixazomib citrate capsules contain a mixture of ixazomib citrate, microcrystalline cellulose, talc, and magnesium stearate.

Tables 1A, 1B, 1C and 2 provide specific embodiments of ixazomib citrate capsules.

The dose strength per capsule at the top of the table refers to the equivalent of ixazomib that is hydrolyzed from ixazomib citrate upon contact with plasma or aqueous solution. For example, a 0.5 mg capsule refers to a capsule containing the equivalent of 0.5 mg ixazomib per capsule. A 2.0 mg capsule refers to a capsule containing the equivalent of 2.0 mg ixazomib per capsule. A 2.3 mg capsule refers to a capsule containing the equivalent of 2.3 mg ixazomib per capsule. A 3.0 mg capsule refers to a capsule containing the equivalent of 3.0 mg ixazomib per capsule. A 4.0 mg capsule refers to a capsule containing the equivalent of 4.0 mg ixazomib per capsule. A 5.0 mg capsule refers to a capsule containing the equivalent of 5.0 mg ixazomib per capsule.

[Table 1A]

[Table 1B]

[Table 1C]

Composition of 0.5mg Ixazomib Citrate Capsules ingredient mg per capsule Ixazomib Citrate 0.72 ^* microcrystalline cellulose 102.70 talc 1.05 Magnesium Stearate 0.53 Gross weight (mg) 105.00 * The amount of Ixazomib Citrate is equivalent to 5.0mg Ixazomib.

In a specific embodiment, a single first dose of ixazomib is administered orally to the patient weekly on days 1, 8, and 15 for 3 weeks, followed by 1 week without ixazomib in a 28-day cycle. . After the first 4 cycles of the 28-day cycle therapy, a second dose of ixazomib is administered to the patient weekly on Days 1, 8, and 15 for Cycles 5 through 26.

In certain embodiments, the first dose of ixazomib is 3.0 mg; The second dose of ixazomib is 4.0 mg.

In certain embodiments, the first dose of ixazomib is 3.0 mg; The second dose of ixazomib is 3.0 mg.

In certain embodiments, the first dose of ixazomib is 2.3 mg; The second dose of ixazomib is 3.0 mg.

In certain embodiments, the first dose of ixazomib is 2.3 mg; The second dose of ixazomib is 2.3 mg.

In certain embodiments, the first dose of ixazomib is 1.5 mg; The second dose of ixazomib is 2.3 mg.

In certain embodiments, the first dose of ixazomib is 1.5 mg; The second dose of ixazomib is 1.5 mg.

In a specific embodiment, the maintenance therapy is given as a single oral dose of 3.0 mg per week on days 1, 8, and 15 initially for 3 weeks, followed by 1 week without ixazomib in a cycle of 28 days. elapse Following the first 4 cycles of therapy, the dose will be increased to 4.0 mg in cycles 5 to 26 in patients who tolerate the drug.

In a specific embodiment, a single 3.0 mg dose of ixazomib is administered orally to the patient weekly on days 1, 8, and 15 for 3 weeks, followed by 1 week without ixazomib in a 28-day cycle. . After the first 4 cycles of the 28-day cycle therapy, a second dose of 3.0 mg ixazomib is administered to the patient weekly on Days 1, 8, and 15 for Cycles 5 through 26.

In a specific embodiment, a single 1.5 mg dose of ixazomib is administered orally to the patient weekly on days 1, 8, and 15 for 3 weeks, followed by 1 week without ixazomib in a 28-day cycle. . After the first 4 cycles of the 28-day cycle therapy, a second dose of 2.3 mg ixazomib is administered to the patient weekly on Days 1, 8, and 15 for Cycles 5 through 26.

Clinical Study of Oral Single-Agent Ixazomib Maintenance Therapy

Twenty-one patients who completed induction therapy received ixazomib maintenance therapy. During induction therapy, patients receive 4.0 mg of ixazomib weekly on days 1, 8, and 15 of a 28-day cycle; He received 25.0 mg of lenalidomide on days 1-21, and 40 mg of dexamethasone weekly on days 1, 8, 15, and 22.

These patients completed induction therapy and progressed to the maintenance phase. 16 patients were started on ixazomib at 4.0 mg; 4 patients started on 3.0 mg ixazomib; One patient was started on 2.4 mg ixazomib. Patients who received maintenance therapy had the characteristics shown in Tables 3 and 4.

patient
characteristic Patients who received maintenance, n=21 Median age, years (range) 68 (34-77) Age ≥65 years, n (%) 12 (57) Age ≥75 years, n (%) 2 (10) male, n (%) 13 (62) Caucasians, n (%) 16 (76) ISS disease stage at diagnosis, n (%) I 14 (67) II 7 (33) III 0 MM subtype, n (%) IgG 16 (76) IgA 3 (14) IgD 0 light chain 2 (10) Median creatinine clearance, ml/min 83.5

cell genetics Patients who received maintenance, n=21 Patients with cytogenetic evaluation, N* 19 normal/karyotype 3 (16) Molecular/FISH 6 (32) both 10 (53) Adverse cytogenetics ^† , n (%) 3 (16) Type of cytogenetic abnormality, n (%) Deletion 13 (by metaphase cytogenetics) 2 (11) fruition 17 1 (5) t(4;14) 0 t(14;16) 1 (5) 1q amplification 0

No samples were collected for 3 patients. ^† Adverse cytogenetics include deletion 17, t(4;14), t(14;16), and 1q amplification detected by FISH or metaphase cytogenetics, and deletion 13 detected by metaphase cytogenetics. Maintenance During the therapy phase, patients received single agent ixazomib for a median of 19 treatment cycles (range 3 to 23), with a median treatment duration of 29.0 months (range 14.3 to 33.3 months). Table 5 shows the therapeutic exposure.

In cutoff data, median cycles of ixazomib received, n (range) Patients who received maintenance, n=21 Total (including induction and maintenance cycles) 31 (15-35) maintenance cycle 19 (3-23) Median duration of treatment, months (range) 29.0 (14.3-33.3) Retention period, months (range) 19.8 (2.3-22.9) Mean Relative Dose Intensity of Ixazomib
Total/during induction/during maintenance, % 92/95/89.5 Patients who continued to maintain ixazomib, n (%) 11 (52%)

2 shows the best overall response in 21 patients who received ixazomib maintenance therapy (n=21). The best overall response was as follows: Complete remission (CR) or better in 52% of patients (11/21). ), and very good partial remission (VGPR) or better in 71% (15/21) of the patients.

Forty-eight percent (48%) of patients had a similar CR (nCR) (2/10) at 2 VGPRs, a CR (5/10) at 5 VGPRs, and a strict complete response (sCR) at 1 VGPR (1/10). 10), and response improvements during maintenance (10/21), including two CR to sCR (2/10) response improvements. The median duration of response was 21.65 months (range 6.7 to 31.18 months).

Fifty-two percent (52%) (11/21) of patients continued to maintain cognate ixazomib after the study's data cutoff.

The median time to first response (≧ rapid response “PR”) was 0.99 months (range 0.92 to 5.78 months) and the median time to best response was 7.46 months (range 1.02 to 24.74 months). Mean ixazomib relative dose intensities were 95 percent (95%) and 89.5 (89.5) percent in the induction and maintenance phases, respectively.

After 25.1 to 33.9 months of follow-up, all patients who received ixazomib maintenance were alive.

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Claims (35)

A pharmaceutical composition comprising a compound of Formula IIIa, or a pharmaceutically acceptable salt thereof, for use as a single agent in maintenance therapy for preventing or delaying cancer recurrence or progression in patients in remission receiving first-line cancer therapy as,
[Formula IIIa]

the cancer is multiple myeloma;
The compound of Formula IIIa, or a pharmaceutically acceptable salt thereof, is used in a dosing schedule comprising at least 19 28-day treatment cycles, each cycle wherein the pharmaceutical composition is administered once per week for the first 3 weeks of the cycle. A pharmaceutical composition comprising 4 weeks of administration once orally and no administration in the 4th week. The pharmaceutical composition according to claim 1, wherein the compound of Formula IIIa, or a pharmaceutically acceptable salt thereof, is administered orally. The pharmaceutical composition according to claim 1, wherein the compound of Formula IIIa, or a pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 in each treatment cycle. The pharmaceutical composition according to claim 1 , wherein the dosing schedule comprises 26 treatment cycles. 5. The pharmaceutical composition of claim 4, wherein the compound of Formula IIIa, or a pharmaceutically acceptable salt thereof, is administered in a first dose for at least 4 treatment cycles and as a second dose in 5 to 26 treatment cycles. composition. 6. The pharmaceutical composition according to claim 5, wherein the first dose is 3.0 mg and the second dose is 4.0 mg. 6. The pharmaceutical composition according to claim 5, wherein the first dose is 3.0 mg and the second dose is 3.0 mg. 6. The pharmaceutical composition according to claim 5, wherein the first dose is 2.3 mg and the second dose is 3.0 mg. 6. The pharmaceutical composition according to claim 5, wherein the first dose is 2.3 mg and the second dose is 2.3 mg. The pharmaceutical composition according to claim 5, wherein the first dose and the second dose are the same. The pharmaceutical composition according to claim 1, wherein the compound of formula IIIa is in solid dosage form. 12. The pharmaceutical composition according to claim 11, wherein the solid dosage form is a capsule. 13. The pharmaceutical composition according to claim 12, wherein the capsule comprises a mixture of ixazomib citrate, microcrystalline cellulose, talc, and magnesium stearate. The pharmaceutical composition of claim 1 , wherein the first-line cancer therapy comprises a proteasome inhibitor-based therapy, or an immunomodulatory drug-based therapy, or both. The pharmaceutical composition according to claim 1 , wherein the primary cancer therapy includes transplantation of autologous stem cells. The pharmaceutical composition according to claim 1, wherein the primary cancer therapy comprises performing autologous stem cell transplantation after proteasome inhibitor-based therapy, or immunomodulatory drug-based therapy, or both. The method of claim 1 , wherein the first-line cancer therapy comprises proteasome inhibitor-based therapy, immunomodulatory drug-based therapy, or both followed by conditioning therapy comprising melphalan and autologous stem cell transplantation. , pharmaceutical composition. 18. The pharmaceutical composition according to claim 16 or 17, wherein the proteasome inhibitor based therapy comprises bortezomib. 18. The pharmaceutical composition according to any one of claims 14, 16 and 17, wherein the immunomodulatory drug based therapy comprises lenalidomide or pomalidomide. 20. The pharmaceutical composition of claim 19, wherein the immunomodulatory drug based therapy comprises lenalidomide. The pharmaceutical composition according to claim 1, wherein the first 28-day treatment cycle begins at least 75 days after autologous stem cell transplantation is performed. The pharmaceutical composition according to claim 1 , wherein the first 28-day treatment cycle begins no later than 115 days after autologous stem cell transplantation is performed. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used for maintenance therapy to treat a patient at risk of recurrence of a cancer selected from multiple myeloma, or suffering from the recurrence. delete delete delete delete delete delete delete delete delete delete delete delete

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